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Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

Primary Purpose

Hypoxic Ischemic Encephalopathy

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Melatonin

Magnetic Resonance Imaging

Pharmacokinetics

Neurological Outcome Assessment

About this trial

This is an interventional treatment trial for Hypoxic Ischemic Encephalopathy

Eligibility Criteria

undefined - 6 Hours (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Eligible infants are >36 0/7th weeks gestation,
pH (cord or neonatal) <7.0,
base deficit >16 mEq/L,
no available blood gas,
a cord blood/first hour of life blood gas with pH > 7.0 and < 7.15,
base deficit between 10 and 15.9 mEq/L,
infants must have a history of an acute perinatal event,
either a 10-minute Apgar < 5 or a continued need for ventilation,
All infants must have signs of encephalopathy within 6 hours of age using the modified Sarnat scoring system,
neonates cooled within 6 hours of birth will be included in the study.

Exclusion Criteria:

suspected inborn errors of metabolism (elevated ammonia) and hypoglycemia,
clinical signs and symptoms consistent with meningitis detected upon sepsis evaluation,
a diagnosis of congenital abdominal surgical problems along with multiple congenital anomalies and/or chromosomal abnormalities.

Sites / Locations

University of FloridaRecruiting
Florida Hospital for ChildrenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Participants 1-10

Participants 11-20

Participants 21-30

Arm Description

This group will receive a 0.5 mg/kg enteral dose of Melatonin. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

This group will the Melatonin dose of 3 mg/kg enteral, only if the group Participants 1-10 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

This group will receive Melatonin dose of 5 mg/kg enterally, only if the group Participants 11-20 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Outcomes

Primary Outcome Measures

To identify the maximum tolerated dose of Melatonin

The maximum tolerated dose (MTD) is defined as the highest dose level without adverse events in no more than 1 out of 6 patients

Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment

All raw scores will be transformed into norm-referenced standard scores (scale mean = 100 with s.d. = 15) using the Bayley-III scoring software published with the test. To dichotomize "good" and "poor" outcomes for statistical analysis, standardized scores that are at or greater than one standard deviation below the normative sample mean published with the test (i.e., standard scores < 85) will be classified as "poor outcome" while higher scores will be classified as "good outcome".

Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.

HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum samples. The two-way ANOVA (treatments are dose level and timepoint) framework for testing. Testing will be done using a likelihood ratio test, either using large-sample theory approximation or using bootstrap.

Number of participants with treatment-related adverse events as assessed by MedDRA ??? This is something the PI/Team needs to agree on which one to use.

Incidence/Grade of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), laboratory abnormalities Percentage and number of subjects who discontinued for adverse event

Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg.

HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum. The two-way ANOVA (treatments are dose level and timepoint) framework for testing. Testing will be done using a likelihood ratio test, either using large-sample theory approximation or using bootstrap.

Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg.

Secondary Outcome Measures

Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment

The four performance-based subscales of the Bayley-III Index Scores (Receptive and Expressive Language, Fine and Gross Motor) and two parent-reported scales (Social-Emotional and Adaptive Behavior) will be collected. All raw scores will be transformed into norm-referenced standard scores (scale mean = 100 with s.d. = 15) using the Bayley-III scoring software published with the test. To dichotomize "good" and "poor" outcomes for statistical analysis, standardized scores that are at or greater than one standard deviation below the normative sample mean published with the test (i.e., standard scores < 85) will be classified as "poor outcome" while higher scores will be classified as "good outcome".

Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)

The MRI study scores of neonates treated with hypothermia plus melatonin will be compared with historical controls that have matched Sarnat exams (exam of HIE severity at the time of admission).

Full Information

NCT ID

NCT02621944

First Posted

October 19, 2015

Last Updated

May 18, 2023

Sponsor

University of Florida

Collaborators

Thrasher Research Fund

1. Study Identification

Unique Protocol Identification Number

NCT02621944

Brief Title

Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

Official Title

Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 2016 (undefined)

Primary Completion Date

March 2025 (Anticipated)

Study Completion Date

March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

Collaborators

Thrasher Research Fund

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Hypoxic-Ischemic Encephalopathy (HIE) occurs in 20 per 1000 births. Only 47% of neonates treated with the state of the art therapy (induced systemic hypothermia) have normal outcomes. Therefore, other promising therapies that potentially work in synergy with hypothermia to improve neurologic outcomes need to be tested. One potential agent is melatonin. Melatonin is a naturally occurring substance produced mainly from the pineal gland. Melatonin is widely known for its role in regulating the circadian rhythm, but it has many other effects that may benefit infants with HI injury. Melatonin serves as a free radical scavenger, decreases inflammatory cytokines, and stimulates anti-oxidant enzymes. Therefore, melatonin may interrupt several key components in the pathophysiology of HIE, in turn minimizing cell death and improving outcomes. The research study will evaluate the neuroprotective properties and appropriate dose of Melatonin to give to infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

Detailed Description

Thirty subjects will be enrolled in a dose escalation study. Subjects 1-10 will receive melatonin (0.5 mg/kg). If that dose proves to be safe, subjects 11-20 will receive an increased dose of melatonin (3 mg/kg). Subjects 21-30 will receive a dose increased to the targeted projected therapeutic dose (5 mg/kg). The serum concentration of melatonin and capture adverse event reports during this dose escalation study in neonates undergoing hypothermia and the long-term safety and potential efficacy via developmental follow-up performed at 18-22 months of age. In addition, this study will determine the effect of melatonin on the inflammatory cascade, oxidative stress, free radical production, and serum biomarkers of brain injury in neonates undergoing hypothermia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypoxic Ischemic Encephalopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Participants 1-10

Arm Type

Experimental

Arm Description

Arm Title

Participants 11-20

Arm Type

Experimental

Arm Description

Arm Title

Participants 21-30

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Melatonin

Intervention Description

Participants 1-10 will receive a 0.5 mg/kg enteral dose of Melatonin. Participants 11-20 will receive Melatonin dose of 3 mg/kg enteral. Participants 21-30 will receive Melatonin dose of 5 mg/kg enterally.

Intervention Type

Other

Intervention Name(s)

Magnetic Resonance Imaging

Other Intervention Name(s)

MRI

Intervention Description

All participants will receive an MRI between 7-12 days of age.

Intervention Type

Other

Intervention Name(s)

Pharmacokinetics

Intervention Description

All participants will receive pharmacokinetics to test the amount of melatonin in the blood.

Intervention Type

Behavioral

Intervention Name(s)

Neurological Outcome Assessment

Intervention Description

All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.

Primary Outcome Measure Information:

Title

To identify the maximum tolerated dose of Melatonin

Description

The maximum tolerated dose (MTD) is defined as the highest dose level without adverse events in no more than 1 out of 6 patients

Time Frame

Changes in Baseline to day 3

Title

Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment

Description

Time Frame

Approximately 18 - 20 Months

Title

Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.

Description

Time Frame

0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

Title

Number of participants with treatment-related adverse events as assessed by MedDRA ??? This is something the PI/Team needs to agree on which one to use.

Description

Incidence/Grade of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), laboratory abnormalities Percentage and number of subjects who discontinued for adverse event

Time Frame

Baseline ongoing to Day 14

Title

Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg.

Description

Time Frame

0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

Title

Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg.

Description

Time Frame

0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

Secondary Outcome Measure Information:

Title

Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment

Description

Time Frame

Approximately 18 - 20 Months

Title

Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)

Description

The MRI study scores of neonates treated with hypothermia plus melatonin will be compared with historical controls that have matched Sarnat exams (exam of HIE severity at the time of admission).

Time Frame

Approximately 7 - 12 days

10. Eligibility

Sex

All

Maximum Age & Unit of Time

6 Hours

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Eligible infants are >36 0/7th weeks gestation, pH (cord or neonatal) <7.0, base deficit >16 mEq/L, no available blood gas, a cord blood/first hour of life blood gas with pH > 7.0 and < 7.15, base deficit between 10 and 15.9 mEq/L, infants must have a history of an acute perinatal event, either a 10-minute Apgar < 5 or a continued need for ventilation, All infants must have signs of encephalopathy within 6 hours of age using the modified Sarnat scoring system, neonates cooled within 6 hours of birth will be included in the study. Exclusion Criteria: suspected inborn errors of metabolism (elevated ammonia) and hypoglycemia, clinical signs and symptoms consistent with meningitis detected upon sepsis evaluation, a diagnosis of congenital abdominal surgical problems along with multiple congenital anomalies and/or chromosomal abnormalities.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Livia Sura, MPH, CPH

Phone

3522738706

livia.sura@peds.ufl.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Kristine Boykin, BSN

Phone

3522738706

kristineboykin@ufl.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael D Weiss, MD

Organizational Affiliation

University of Florida

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kristine L Boykin, BSN

Phone

352-273-8985

kristineboykin@ufl.edu

First Name & Middle Initial & Last Name & Degree

Michael Weiss, MD

Phone

3522738985

weissmd@peds.ufl.edu

First Name & Middle Initial & Last Name & Degree

Michael D Weiss, MD

First Name & Middle Initial & Last Name & Degree

Giuseppe Buonocore, MD

First Name & Middle Initial & Last Name & Degree

Candace Rossignol, Sr. Lab Tech

First Name & Middle Initial & Last Name & Degree

Ronald Hayes, MD

First Name & Middle Initial & Last Name & Degree

Kristine Boykin, BSN

First Name & Middle Initial & Last Name & Degree

Rajan Wadhawan, MD

First Name & Middle Initial & Last Name & Degree

Nicole Copenhaver, BA, ASN

First Name & Middle Initial & Last Name & Degree

Ganna Zalevska, BS, RRT

Facility Name

Florida Hospital for Children

City

Orlando

State/Province

Florida

ZIP/Postal Code

32803

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Rajan Wadhawan, M.D.

Phone

407-303-2528

Rajan.Wadhawan.MD@flhosp.org

First Name & Middle Initial & Last Name & Degree

Rajan Wadhawan, MD

12. IPD Sharing Statement

Learn more about this trial

Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

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